Hepatic Lipid Accumulation and Nrf2 Expression following Perinatal and Peripubertal Exposure to Bisphenol A in a Mouse Model of Nonalcoholic Liver Disease
| Autor: | Angela L. Slitt, Ajay C. Donepudi, Maneesha Paranjpe, Beverly S. Rubin, Prajakta Shimpi, Dana C. Dolinoy, Vijay R. More, Jaclyn M. Goodrich |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Bisphenol A Health Toxicology and Mutagenesis 010501 environmental sciences 01 natural sciences Epigenesis Genetic Mice chemistry.chemical_compound Liver disease Non-alcoholic Fatty Liver Disease Pregnancy Lactation Nonalcoholic fatty liver disease Medicine Fatty liver 3. Good health medicine.anatomical_structure Liver Prenatal Exposure Delayed Effects Environmental Pollutants Female Sterol Regulatory Element Binding Protein 1 hormones hormone substitutes and hormone antagonists endocrine system medicine.medical_specialty NF-E2-Related Factor 2 digestive system 03 medical and health sciences Phenols Internal medicine Animals Humans Benzhydryl Compounds Adverse effect 0105 earth and related environmental sciences urogenital system business.industry Research Puberty Public Health Environmental and Occupational Health DNA Methylation Lipid Metabolism medicine.disease Disease Models Animal 030104 developmental biology Endocrinology chemistry Hepatic lipid business |
| Zdroj: | Environmental Health Perspectives |
| ISSN: | 1552-9924 0091-6765 |
| DOI: | 10.1289/ehp664 |
| Popis: | Background: Exposure to chemicals during critical windows of development may re-program liver for increased risk of nonalcoholic fatty liver disease (NAFLD). Bisphenol A (BPA), a plastics component, has been described to impart adverse effects during gestational and lactational exposure. Our work has pointed to nuclear factor E2-related factor 2 (Nrf2) being a modulator of hepatic lipid accumulation in models of NAFLD. Objectives: To determine if chemical exposure can prime liver for steatosis via modulation of NRF2 and epigenetic mechanisms. Methods: Utilizing BPA as a model exposure, pregnant CD-1 mice were administered 25μg/kg/day BPA via osmotic minipumps from gestational day 8 through postnatal day (PND)16. The offspring were weaned on PND21 and exposed to same dose of BPA via their drinking water through PND35. Tissues were collected from pups at week 5 (W5), and their littermates at week 39 (W39). Results: BPA increased hepatic lipid content concomitant with increased Nrf2 and pro-lipogenic enzyme expression at W5 and W39 in female offspring. BPA exposure increased Nrf2 binding to a putative antioxidant response element consensus sequence in the sterol regulatory-element binding protein-1c (Srebp-1c) promoter. Known Nrf2 activators increased SREBP-1C promoter reporter activity in HepG2 cells. Methylated DNA immunoprecipitation-PCR and pyrosequencing revealed that developmental BPA exposure induced hypomethylation of the Nrf2 and Srebp-1c promoters in livers of W5 mice, which was more prominent in W39 mice than in others. Conclusion: Exposure to a xenobiotic during early development induced persistent fat accumulation via hypomethylation of lipogenic genes. Moreover, increased Nrf2 recruitment to the Srebp-1c promoter in livers of BPA-exposed mice was observed. Overall, the underlying mechanisms described a broader impact beyond BPA exposure and can be applied to understand other models of NAFLD. https://doi.org/10.1289/EHP664 |
| Databáze: | OpenAIRE |
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